Background

Patients with familial hypercholesterolaemia (FH) are at increased risk for premature cardiovascular disease (CVD) as a result of high LDL-c plasma levels, but it has been noticed that they may be less prone to develop type 2 diabetes mellitus (T2DM).
Statin use is associated with increased risk for T2DM [1], and so is a genetic variation at the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) locus [2]. Statins inhibit HMGCR, which leads to increased LDL receptor (LDLR) expression and which promotes transmembrane cholesterol transport [3]. In FH, the opposite situation is the case, namely genetically impaired cellular cholesterol uptake.
This study tested the hypothesis that the prevalence of T2DM is decreased in patients with FH, because their pancreatic beta cells have decreased cholesterol uptake and therefore improved function and survival. The study benefitted from the registry of the national Dutch FH screening program. The different mutations causing varied clinical phenotypes [4] allow for exploring a dose-response relationship. In this study, the prevalence of T2DM was compared between patients with FH (n=25 137) and their unaffected relatives (n=38 183).

Main results

The observed T2DM prevalence was lower in patients with FH (1.75%, 95%CI: 1.59-1.91%) than in their unaffected relatives (2.93%, 95%CI: 2.76-3.10%, P=<0.001).
After adjustment for multiple risk factors the difference in prevalence of T2DM was even larger (in patients with FH: 1.44% [95%CI: 1.22-1.69] vs. unaffected: 3.26% [95%CI: 3.04-3.48].

Adj ORs for T2DM as compared to unaffected relatives were different depending on whether patients were receptor-defective (0.49, 95%CI: 0.40-0.60) or receptor-negative (0.38, 95%CI: 0.289-0.49).

Conclusion

This study in 25 000 patients with FH and 38 000 unaffected relatives shows that the prevalence of type 2 diabetes is significantly lower in patients with FH. An inverse dose-response relationship was observed between the severity of the mutation underlying FH and the prevalence of T2DM.
The small absolute difference in prevalence in T2DM between FH patients and unaffected relatives means that it will not have a substantial impact on an individual’s risk. The larger relative difference, however, supports the hypothesis that the common pathway in FH and statin therapy – cellular cholesterol uptake – is implicated in the development of type 2 diabetes.

Editorial comment [5]

“The authors acknowledge several important weaknesses in the study (…). Nonetheless, no better study currently exists to address this question, and the fact that this massive cohort is dominated by cascaded family members, divided into groups with familial hypercholesterolemia and without based on mutation status, which is randomly allocated at birth, should limit the influence of confounders compared with conventional observational studies. (…) This report adds to the growing literature of a complex interplay between lipids, glycemia, and adiposity, in which statins and other lipid-modifying agents appear to affect diabetes risk. The study also provides mechanistic insight into the potential roles of the LDL receptor and intracellular cholesterol accumulation. From a clinical perspective, the findings should allay any concerns about the potential diabetogenic effect of statins when treating patients with familial hypercholesterolemia from childhood or young adulthood given that these patients appear to be at a low risk for diabetes. Most intriguingly, the results suggest that the expression and function of LDL receptors may be important for glucose homeostasis.(…) However, the LDL receptor is widely expressed, and skeletal muscle, the liver, and adipose tissue may yet prove to be involved. The advent of potent LDL cholesterol–lowering agents such as PCSK9 inhibitors provides an important opportunity to further examine the link between LDL receptor expression and glycemia, adiposity, and diabetes risk.”